Immune modulation to clear amyloid-beta (AB) is a promising therapy for Alzheimer's disease (AD). Although a clinical trial on this approach was recently halted because of T-cell related encephalitis in a small subset of patients, its preliminary findings indicate cognitive stabilization and clearance of brain AB deposits. During the first years of this grant, and prior to the adverse reactions in the trial, we have been assessing various AB derivatives as a safer approach for AD immunotherapy. All our vaccines improve cognition in transgenic (tg) mice indicating that these homologs are good candidates for clinical trials. Prior to this, non-human primate studies are warranted because their immune system and AB levels are closer to humans than the mouse equivalent. Hence, Specific Aim 1 is: To assess potential therapeutic benefits and side effects, in particular T-cell toxicity and cerebral bleeding, of AB derivative immunotherapy in lemur primates. We will determine: 1) the immune response;2) AB levels in plasma and urine;3) cognitive effects;4) potential acute and chronic toxicity;and 5) brain amyloid burden and associated pathology following immunization with AB derivative immunogens in lemur primates (Microcebus murinus). In addition to histological and biochemical analysis at the end of the study, treatment efficacy and potential cerebral bleeding will be evaluated in vivo by brain imaging. We have developed MRI probes that allow us to detect brain amyloid plaques in vivo. This technology is ideally suited to monitor treatment efficacy in vivo. Because of the paramagnetic nature of iron, this method will also be useful to monitor potential cerebral bleeding. To avoid possible T-cell adverse effects, clinical AB antibody trials are underway but cerebral bleeding has been observed with this approach in tg mice. Specific Aim 2 is: A) To clarify the mechanism of cerebral microhemorrhages following AB antibody therapy and;B) To compare strategies to avoid this side effect while promoting AB clearance. Towards this end, tg mouse models that primarily develop vascular- or parenchymal AB deposits will be immunized with anti-AB antibodies or AB derivatives. Treatment efficacy and potential cerebral bleeding will be monitored with magnetic resonance imaging (MRI) and with histological and biochemical analyses at the end of the study. The animals will undergo extensive behavioral assessment as well. We will determine in tg mice if the bleeding is related to removal of vascular or parenchymal amyloid. Treatment with proteolytic antibodies that cleave AB is less likely to have this side effect, and we have not observed bleeding with our active immunization approach further supporting its feasibility for human use. Overall, these studies should provide valuable information on which type of immunotherapy is likely to be safe and effective, and should identify the appropriate AB-targeting immunotherapy for use in clinical trials.

Public Health Relevance

The aim of the proposed studies is to continue our development of a safe immunotherapy targeting amyloid-beta, a major hallmark of Alzheimer's disease (AD). The first aim will be performed in lemur primates, a model of AD, to verify the safety profile of our AB derivatives prior to clinical trials. The second aim will be performed in transgenic mouse models of AD because of the larger number of animals required and/or because of the earlier developmental stage of those approaches.